Newcastle, England — Iksuda Therapeutics has received clearance from the U.S. Food and Drug Administration for its Investigational New Drug application for IKS04, allowing the company to begin Phase 1 clinical testing of the antibody-drug conjugate in patients with gastrointestinal cancers.
IKS04 is a CA242-directed antibody-drug conjugate, or ADC, being developed for cancers including colorectal, gastric, pancreatic and biliary tract cancers.
CA242 is a tumor-specific glycotope that is strongly expressed in many gastrointestinal cancers, including most colorectal, gastric, pancreatic and biliary tract tumors. It is also found in about half of bladder, endometrial and lung cancers, while showing limited expression in normal tissue.
Previous efforts to target CA242 using ADCs carrying tubulin inhibitor payloads have demonstrated limited clinical efficacy, potentially because gastrointestinal cancers can be resistant to that mechanism. ADCs using topoisomerase I inhibitor payloads have also had limited success in cancers of the colon and stomach.
Iksuda said IKS04 was designed to address the need for more potent ADCs with differentiated tumor-killing mechanisms and novel targets.
The treatment combines a humanized anti-CA242 antibody with a highly potent pyrrolobenzodiazepine, or PBD, prodrug payload.
Highly potent payloads such as PBDs can restrict the maximum tolerated dose of an ADC because of systemic side effects. Lower dosing may then limit how deeply the treatment penetrates solid tumors, particularly tumors with high levels of the targeted antigen.
To address that challenge, IKS04 will be administered alongside an unconjugated anti-CA242 antibody. Iksuda said the approach is intended to overcome the antigen barrier and improve penetration of the ADC into solid tumors. The company described the strategy, known as the IKS04 Regimen, as a first for the ADC field and similar to dosing methods used in radioimmunotherapy.
Preclinical studies showed activity across a range of gastrointestinal cancer models and a favorable therapeutic index. Iksuda said IKS04 demonstrated the widest preclinical therapeutic index among PBD-containing ADCs developed for solid tumors.
Anticancer activity was further improved in models with high CA242 expression when IKS04 was administered with the unconjugated anti-CA242 antibody, supporting the proposed dosing regimen.
“This IND clearance for IKS04 and the IKS04 Regimen is another important step for Iksuda and further validation of our approach to designing and developing innovative ADCs with the optimal clinical calibration for a given target and indication,” said Dave Simpson, Ph.D., Chief Executive Officer of Iksuda Therapeutics.
“IKS04 will be Iksuda’s third ADC to enter clinical development, a significant milestone for the company, with IKS014 and IKS03 both currently progressing through Phase 1 studies,” Simpson added. “This demonstrates the value of our expanding, innovative platforms and further de-risks the clinical advancement of our novel antibodies, linkers and payloads.”
Iksuda’s ADC development strategy involves selecting combinations of antibodies, conjugation technologies, linkers and payload mechanisms based on the targeted cancer and clinical indication.
IKS04 incorporates prodrug technology designed to enable tumor-selective activation and payload release through glucuronide triggers. The company said the approach is intended to improve tolerability compared with traditional linker formats.
The technology has also been incorporated into IKS014, a HER2-directed ADC containing an MMAF payload, and IKS03, a CD19-directed ADC containing the same PBD prodrug used in IKS04. Both candidates are currently in Phase 1 clinical development.
“IKS04 is directed at a novel target in difficult-to-treat GI cancers,” said Leon Pappas, an investigator at Massachusetts General Hospital. “The co-administration regimen and PBD payload are a distinctive approach, and the clinical program will investigate whether they can thereby deliver a better balance of efficacy and tolerability.”
Pappas added that he was eager to see whether the approach could benefit patients as IKS04 advances through clinical development.
